Insoluble alpha-synuclein in Alzheimer's disease without Lewy body formation.

Insoluble alpha-synuclein plays a central role in Lewy body diseases, with considerable controversy as to whether it plays a similar role in Alzheimer's disease (AD). We assessed the tissue location and solubility of cortical alpha-synuclein in AD (without Lewy body formation) compared with controls, using sequential extraction procedures and Western immunoblotting to quantify different alpha-synuclein species in their different solubility states. Controls had no insoluble cortical alpha-synuclein and a ratio of soluble:lipid-associated alpha-synuclein of 1.2-/+0.1. Total alpha-synuclein protein was significantly increased in AD and concentrated within the lipid-associated fraction (soluble:lipid ratio 0.9-/+0.05, soluble:insoluble 1.5-/+0.1, lipid:insoluble 1.7-/+0.1) which proved difficult to localize in paraffin-embedded tissue. Tissues prepared without lipid extraction revealed alpha-synuclein-immunoreactivity in the amorphous components of mature cored AD plaques. This lipid-association of alpha-synuclein in mature AD plaques links this protein with other lipid changes thought to be important in disease pathogenesis.